This invention relates to a new composition of matter which comprises epoxybutene (EpB) derivatives of cyclodextrins (HBenCD) or mixed ethers of cyclodextrins where at least one of the ether substituents is EpB (HBenRCD where R is an ether substituent other than EpB). This invention also relates to two novel processes for the preparation of cyclodextrin ethers. This invention further relates to inclusion complexes formed between HBenCD or HBenRCD and guest molecules. Such inclusion complexes are useful in pharmaceutical, cosmetic and food applications. Furthermore, this invention relates to the incorporation of HBenCD or HBenRCD or their inclusion complexes in thermoplastic materials, textiles or membranes.
Cyclodextrins (CD) are cyclic oligomers of glucose which typically contain 6, 7, or 8 glucose monomers joined by xcex1-1,4 linkages. These oligomers are commonly called xcex1-CD, xcex2-CD, and xcex3-CD, respectively. Higher oligomers containing up to 12 glucose monomers are known, but their preparation is more difficult.
Those skilled in the art of modifying cyclodextrins will understand that there are a number of ways to indicate the extent to which a cyclodextrin molecule has been modified. Each glucose unit of the cyclodextrin has three hydroxyls available at the 2, 3, and 6 positions. Hence, xcex1-cyclodextrin has 18 hydroxyls or 18 substitution sites available and can have a maximum degree of substitution (DS) of 18. Similarly, xcex2- and xcex3-cyclodextrin have a maximum DS of 21 and 24, respectively.
It should be noted that at less than full substitution, there will be a distribution of substituted CD molecules in the reaction product. At a low DS, some of the CD molecules potentially will have no substituents. The reported DS will reflect the average value of this distribution.
Topologically, CD can be represented as a toroid in which the primary hydroxyls are located on the smaller circumference, and the secondary hydroxyls are located on the larger circumference. Because of this arrangement, the interior of the torus is hydrophobic while the exterior is sufficiently hydrophilic to allow the CD to be dissolved in water. This difference between the interior and exterior faces allows the CD to act as a host molecule and to form inclusion complexes with guest molecules, provided the guest molecule is of the proper size to fit in the cavity. The CD inclusion complex can then be dissolved in water thereby providing for the introduction of insoluble or sparingly soluble guest molecule into an aqueous environment. This property makes CD particularly useful in the pharmaceutical, cosmetic and food industries. Reviews of CD complexes can be found in Chem. Rev., 1997, 97, 1325-1357 and in Supramolecular Chemistry, 1995, 6, 217-223.
The production of CD involves first treating starch with an xcex1-amylase to partially lower the molecular weight of the starch followed by treatment with an enzyme known as cyclodextrin glucosyl transferase which forms the cyclic structure. By conducting the reaction in the presence of selected organic compounds, e.g., toluene, crystalline CD complexes can be formed which facilitate isolation of CD with predetermined ring size. This process has been extensively reviewed by Szejtli et al., Compr. Supramol. Chem., 1996, 3, 41-56. This process yields the native CD discussed above. Table 1 provides a summary of selected physical properties of cyclodextrins.
As seen in Table 1, there is an unexpected drop in solubility in water for xcex2-CD relative to the xcex1- and xcex3-CD. This is most unfortunate as xcex2-CD has a highly desirable cavity size and is the most abundant CD available. Many investigators have found that this difficulty can be somewhat overcome by preparing derivatives with low DS (typically lower than 7).
Although many CD derivatives are known, ethers prepared by displacement of halides (U.S. Pat. No. 4,638,058) or by opening of epoxides (U.S. Pat. No. 4,727,064) are preferred. In special cases, the ether may be polyhydroxylated (EP 486445 A2). Preferred methods of ether formation via epoxide opening are disclosed in U.S. Pat. Nos. 3,459,731 and 4,727,064. The preferred epoxides are ethylene oxide (EO) and propylene oxide (PO). It is important to note that opening of the epoxide generates a new primary hydroxyl (from EO) or secondary hydroxyl (from PO). These newly formed hydroxyls can, in turn, react with epoxide, as well, to form oligomeric side chains. Such derivatives are characterized by molar substitution (MS), which is the total number of epoxide groups attached to the cyclodextrin. Because of chain extension, MS can exceed the DS. Other than the hydroxyls formed by opening of the epoxide, these side chains do not contain functionality suitable for further reactions. Investigators have sought to overcome this limitation by incorporation of anionic or cationic groups as part of the starting epoxide (U.S. Pat. No. 3,453,257).
In addition to their utility in the pharmaceutical, cosmetic, and food industries, CD has begun to find utility in the plastic and textile industries. For example, U.S. Pat. No. 5,603,974 discloses a barrier film composition comprised of a thermoplastic and a substituted CD. It was necessary that the CD be substituted in order to obtain sufficient compatibility with the thermoplastic. The invention further required that the substituted CD be xe2x80x9csubstantially free of an inclusion complexxe2x80x9d meaning that a large fraction of the dispersed CD derivative in the film did not contain a guest molecule. This film acts as a barrier to permeants such as water, aliphatic and aromatic hydrocarbons, carboxylic acids, aldehydes, and the like.
Similarly, WO97/30122 discloses a thermoplastic/CD composition for rigid polymer beverage bottles. The preferred thermoplastic is polyethylene terephthalate (PET), and the preferred CD derivatives are acetylated and trimethylsilylated CD. Like U.S. Pat. No. 5,603,974, this invention requires that a guest molecule not be hosted by the CD prior to compounding.
In EP 186,146, the formation of CD complexes with perfumes, insecticides, or fungicides and their incorporation into polyethylene are disclosed. JP 88-265,926 discloses transparent plastics containing slow-release inclusion complexes prepared by mixing polyesters with maltosyl CD complexes of perfumes, insecticides, and the like. The maltosyl CD complexes were reported to give greater transparency than the corresponding complexes prepared from xcex1-, xcex2-, or xcex3-CD.
JP 01-149,884 discloses sustained-release insecticides, air fresheners, deodorants, etc. in the form of sheet, tape or fiber. Mixing the appropriate CD complex with a plastic material and a water-absorbing polymer forms these sustained-release materials. JP 02-240,166 discloses the preparation and application of complexes of CD and deodorants in the manufacture of plastic products like trash bags.
3,4-Epoxy-1-butene (EpB) is formed by the monoepoxidation of butadiene (U.S. Pat. No. 4,897,498). Ring opening of this epoxide with a lower aliphatic alcohol under acidic conditions leads to the formation of 2-alkoxy-3-butene-1-ols. Under basic conditions, formation of 1-alkoxy-3-butene-2-ols is favored. These butenols can be further reacted with acrylic or methacrylic acids to form acrylic esters, which may be used in subsequent polymerization reactions (U.S. Pat. No. 2,504,082).
Also, the reaction of 3,4-epoxy-1-butene with an oxygen nucleophile in the presence of a Pd(0) complex catalyst leads to the formation of 1,4-dioxy-2-butenes (U.S. Pat. No. 5,189,199). Furthermore, polymerization of 3,4-epoxy-1-butene in the presence of tetrahydrofuran, an acid catalyst, and a nucleophilic initiator provides for the formation of novel polyether compounds (U.S. Pat. No. 5,502,137). All of the products of these reactions are unsaturated, thus providing a functionality useful for further reactions. For example, U.S. Pat. No. 5,502,137 discloses that an unsaturated polyether can be reduced with hydrogen to provide a unique, fully saturated polyether with useful and beneficial properties.
Given the general utility of cyclodextrins in a wide variety of applications, there exists a general need for new CD derivatives that could be utilized in the formation of inclusion complexes. Such inclusion complexes could be preformed for delivery of guest molecules, or the inclusion complexes could be formed as the result of trapping of an unwanted molecule. It would be advantageous if these new CD derivatives could be incorporated into shaped articles. It would be particularly advantageous if the CD derivative contained functionality that would permit further elaboration. We have found that such derivatives can be obtained through the reaction of 3,4-epoxy-1-butene with xcex1-, xcex2-, or xcex3-CD.
This invention relates to new compositions of matter, processes for producing new compositions of matter, inclusion complexes comprised of the new compositions of matter and guest molecules, and shaped articles containing inclusion complexes comprised of the new compositions of matter and guest molecules. Specifically, the invention is directed to:
1. A water-soluble host molecule comprised of hydroxybutenyl derivatives of cyclodextrins (HBenCD) or mixed ethers of cyclodextrins where at least one of the ether substituents is hydroxybutenyl (HBenRCD where R is an ether substituent other than hydroxybutenyl) characterized by having DS of about 0.02 to about 9.0 and capable of forming host-guest complexes.
2. An organic solvent miscible host molecule comprised of hydroxybutenyl derivatives of cyclodextrins (HBenCD) or mixed ethers of cyclodextrins where at least one of the ether substituents is hydroxybutenyl (HBenRCD where R is an ether substituent other than hydroxybutenyl) characterized by having DS of about 9.0 to about 18-24 (depending on the type of cyclodextrin utilized) and capable of forming host-guest complexes.
3. Novel processes for the preparation of cyclodextrin ethers.
4. Inclusion complexes comprised of water-soluble HBenCD or HBenRCD and guest molecules wherein HBenCD and HBenRCD (where R is an ether substituent other than hydroxybutenyl) are characterized by having DS of about 0.02 to about 9.0.
5. Inclusion complexes comprised of an organic solvent miscible HBenCD or HBenRCD and guest molecules wherein HBenCD and HBenRCD (where R is an ether substituent other than hydroxybutenyl) are characterized by having DS of about 9.0 to about 18-24 (depending on the cyclodextrin used).
6. Shaped articles containing from about 0.01% to about 10% of one or more inclusion complexes comprised of HBenCD or HBenRCD and guest molecules.